Guidance for Industry
`
`Clinical Trial Endpoints
`
`for the Approval of Cancer
`
`Drugs and Biologics
`
`
`
`
`
`
`
`U.S. Department of Health and Human Services
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research (CDER)
`
`Center for Biologics Evaluation and Research (CBER)
`
`
`May 2007
`
`Clinical/Medical
`
`
`
`
`
`
`NPC02232922
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`NOVARTIS EXHIBIT 2150
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`Page 1 of 22
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`

`
`Guidance for Industry
`
`Clinical Trial Endpoints
`
`for the Approval of Cancer
`
`Drugs and Biologics
`
`
`
`Additional copies are available from:
`
`
`
`
`
`Office of Training and Communications
`
`
`
`Division of Drug Information, HFD-240
`
`
`
`Center for Drug Evaluation and Research
`
`
`Food and Drug Administration
`
`5600 Fishers Lane
`
`
`Rockville, MD 20857
`
`
`(Tel) 301-827-4573
`
`http://www.fda.gov/cder/guidance/index.htm
`
`
`
`
`or
`
`
`
`Office of Communication, Training, and
`
`Manufacturers Assistance, HFM-40
`
`Center for Biologics Evaluation and Research
`
`
`Food and Drug Administration
`
`
`1401 Rockville Pike, Rockville, MD 20852-1448
`
`
`
`(Tel) 800-835-4709 or 301-827-1800
`
`
`http://www.fda.gov/cber/guidelines.htm
`
`
`
`
`U.S. Department of Health and Human Services
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research (CDER)
`
`Center for Biologics Evaluation and Research (CBER)
`
`
`May 2007
`
`Clinical/Medical
`
`
`
`
`
`
`NPC02232923
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`
`
`TABLE OF CONTENTS
`
`
`
` I.
`INTRODUCTION............................................................................................................. 1
`
`
`
`BACKGROUND ............................................................................................................... 2
`
`II.
`
`
`
`
`A. Regulatory Requirements for Effectiveness ................................................................................2
`
`
`
`B. Endpoints Supporting Past Approvals in Oncology ...................................................................3
`
`III. GENERAL ENDPOINT CONSIDERATIONS ............................................................. 4
`
`
`
`
`
`A. Overall Survival .............................................................................................................................5
`
`
`
`B. Endpoints Based on Tumor Assessments.....................................................................................6
`
`
`
`1. Disease-Free Survival......................................................................................................................6
`
`
`
`2. Objective Response Rate..................................................................................................................7
`
`
`
`3. Time to Progression and Progression-Free Survival ......................................................................8
`
`
`
`a. TTP vs. PFS..............................................................................................................................8
`
`
`
`b. PFS as an endpoint to support drug approval ...........................................................................8
`
`
`
`c. PFS trial design issues ..............................................................................................................8
`
`
`
`d. Analysis of PFS ........................................................................................................................9
`
`
`
`4. Time-to-Treatment Failure ..............................................................................................................9
`
`
`
`C. Endpoints Involving Symptom Assessment...............................................................................10
`
`
`
`1. Specific Symptom Endpoints..........................................................................................................10
`
`
`
`2. Problems Encountered with Symptom Data ..................................................................................10
`
`
`
`D. Biomarkers ...................................................................................................................................11
`
`IV. CLINICAL TRIAL DESIGN CONSIDERATIONS ................................................... 11
`
`
`
`
`
`A. Single-Arm Studies ......................................................................................................................11
`
`
`
`B. Studies Designed to Demonstrate Noninferiority......................................................................11
`
`
`
`C. Trial Designs for Radiotherapy Protectants and Chemotherapy Protectants .......................12
`
`CONCLUSION ............................................................................................................... 12
`
`V.
`
`
`APPENDIX 1: TUMOR MEASUREMENT DATA COLLECTION.................................... 14
`
`
`
`APPENDIX 2: ISSUES TO CONSIDER IN PFS ANALYSIS ............................................... 15
`
`
`
`APPENDIX 3: EXAMPLE TABLES FOR PFS ANALYSIS................................................. 17
`
`
`
`APPENDIX 4: INDEPENDENT REVIEW OF TUMOR ENDPOINTS............................... 19
`
`
`
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`
`Contains Nonbinding Recommendations
`
`Guidance for Industry1
`
`Clinical Trial Endpoints for the Approval
`
`of Cancer Drugs and Biologics
`
`
`
`
`
`
`This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`
`You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
`and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
`implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
`number listed on the title page of this guidance.
`
`
`
`INTRODUCTION
`
`
`
`I.
`
`This guidance is the first in a planned series of cancer endpoint guidances. It provides
`recommendations to applicants on endpoints for cancer clinical trials submitted to the Food and
`Drug Administration (FDA) to support effectiveness claims in new drug applications (NDAs),
`biologics license applications (BLAs), or supplemental applications.2 It also provides
`background information and discusses general regulatory principles. The endpoints discussed in
`this guidance are for drugs to treat patients with an existing cancer. This guidance does not
`address endpoints for drugs to prevent or decrease the incidence of cancer.
`
`
`The FDA is developing guidance on oncology endpoints through a process that includes public
`workshops and discussions before the FDA’s Oncologic Drugs Advisory Committee (ODAC).3
`
`Each subsequent guidance will focus on endpoints for specific cancer types (e.g., lung cancer,
`colon cancer) to support drug approval or labeling claims.
`
`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`
`
` 1 This guidance has been prepared by the Division of Drug Oncology Products and the Division of Biologic
`
`
`
` Oncology Products in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for
`
` Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
`
`
`2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless
`
`
`otherwise specified.
`
`
`3 Transcripts are available at http://www.fda.gov/cder/drug/cancer_endpoints/default.htm.
`
`
`
`
`1
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`BACKGROUND
`
`
`
`II.
`
`Clinical trial endpoints serve different purposes. In conventional oncology drug development,
`early phase clinical trials evaluate safety and identify evidence of biological drug activity, such
`as tumor shrinkage. Endpoints for later phase efficacy studies commonly evaluate whether a
`drug provides a clinical benefit such as prolongation of survival or an improvement in
`symptoms. The following sections discuss the general regulatory requirements for efficacy and
`how they have influenced endpoint selection for the approval of cancer drugs. Later sections
`describe these endpoints in more detail and discuss whether they might serve as measures of
`disease activity or clinical benefit in various clinical settings.
`
`
`
`A.
`
`Regulatory Requirements for Effectiveness
`
`The requirement that new drugs show effectiveness is based on a 1962 amendment to the Federal
`Food, Drug, and Cosmetic Act. This law requires substantial evidence of effectiveness and
`specifies that this evidence must be derived from adequate and well-controlled clinical
`
`investigations. Similarly, the Public Health Service Act requires biological products to be safe,
`pure, and potent. Clinical benefits that have supported drug approval have included important
`clinical outcomes (e.g., increased survival, symptomatic improvement) but have also included
`effects on established surrogate endpoints (e.g., blood pressure, serum cholesterol).
`
`The accelerated approval regulations (21 CFR part 314, subpart H and 21 CFR part 601, subpart
`E), promulgated in 1992, allow use of additional endpoints for approval of drugs or biological
`products that are intended to treat serious or life-threatening diseases and that either demonstrate
`an improvement over available therapy or provide therapy where none exists. In this setting, the
`FDA may grant approval based on an effect on a surrogate endpoint that is reasonably likely to
`predict clinical benefit (“based on epidemiologic, therapeutic, pathophysiologic, or other
`evidence”). Such surrogates are less well-established than surrogates in regular use, such as
`blood pressure or cholesterol for cardiovascular disease. A drug is approved under the
`accelerated approval regulations on condition that the manufacturer conducts clinical studies to
`verify and describe the actual clinical benefit. If the postmarketing studies fail to demonstrate
`clinical benefit or if the applicant does not demonstrate due diligence in conducting the required
`studies, the drug may be removed from the market under an expedited process. In the following
`discussion, the term regular approval denotes the longstanding route of drug approval based on
`
`the demonstration of clinical benefit. That term is distinguished from accelerated approval,
`
`which is associated with use of a surrogate endpoint that is reasonably likely to predict benefit.
`
`The evidence critical for supporting drug approval, including the preferred number of clinical
`trials, is discussed in the guidance for industry FDA Approval of New Cancer Treatment Uses for
`Marketed Drug and Biological Products4 and in the FDA Modernization Act of 1997.5 In most
`
`
`
` 4 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER
`
`
` guidance Web page at http://www.fda.gov/cder/guidance/index.htm.
`
`
`
`5 http://www.fda.gov/cder/fdama/default.htm
`
`
`
`
`
`2
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`cases, the FDA recommends at least two adequate and well-controlled clinical trials. In certain
`cases, evidence from a single trial can be sufficient (e.g., in cases in which a single multicenter
`study provides highly reliable and statistically strong evidence of an important clinical benefit,
`such as an effect on survival, and in which confirmation of the result in a second trial would be
`practically or ethically impossible). For drugs approved for treatment of patients with a specific
`stage of a particular malignancy, evidence from one trial may be sufficient to support an efficacy
`supplement for treatment of a different stage of the same cancer.
`
`
`
`B.
`
`Endpoints Supporting Past Approvals in Oncology
`
`For regular approval, it is critical that the applicant show direct evidence of clinical benefit or
`improvement in an established surrogate for clinical benefit. In oncology, survival improvement
`is considered an appropriate measure of clinical benefit. In addition, sponsors have used other
`endpoints for cancer drug approval. In the 1970s, the FDA usually approved cancer drugs based
`on objective response rate (ORR), determined by tumor assessments from radiological tests or
`physical examinations. In the early 1980s, after discussion with the ODAC, the FDA determined
`
`that cancer drug approval should be based on more direct evidence of clinical benefit, such as
`improvement in survival, improvement in a patient’s quality of life (QOL), improved physical
`functioning, or improved tumor-related symptoms. These benefits may not always be predicted
`by, or correlate with, ORR.
`
`Over the next decade, several endpoints were used as established surrogates for clinical benefit.
`Improvement in disease-free survival (DFS) supported drug approval in selected adjuvant
`settings, in which a large proportion of patients were expected to have cancer symptoms at the
`time of recurrence. Durable complete response was considered an established endpoint of
`clinical benefit in leukemia, where complete response is associated with less infection, bleeding,
`and blood product support. A high, substantiated ORR can support regular approval in select
`solid tumors, but that response duration, relief of tumor-related symptoms, and drug toxicity also
`should be considered when making the approval decision (O’Shaughnessy and Wittes et al.,
`1991, Commentary Concerning Demonstration of Safety and Efficacy of Investigational
`Anticancer Agents in Clinical Trials, J Clin Oncol, 9:2225-2232). For example, randomized
`trials for hormonal drugs for breast cancer have used ORR as an endpoint supporting regular
`approval. Improvement in tumor-related symptoms in conjunction with an improved ORR and
`adequate response duration has supported regular approval in several clinical settings.
`
`Surrogate endpoints for accelerated approval must be reasonably likely to predict clinical benefit
`(21 CFR part 314, subpart H and 21 CFR part 601, subpart E). Such drugs also must provide a
`benefit over available therapy (21 CFR part 314, subpart H and 21 CFR part 601, subpart E).6
`
`ORR has been the most commonly used surrogate endpoint in support of accelerated approval.
`Tumor response is widely accepted by oncologists in guiding cancer treatments. Because ORR
`is directly attributable to drug effect, single-arm trials conducted in patients with refractory
`tumors where no available therapy exists provide an accurate assessment of ORR.
`
`
`6 See the guidance for industry Available Therapy (http://www.fda.gov/cder/guidance/index.htm).
`
`
`
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`
`
`III. GENERAL ENDPOINT CONSIDERATIONS
`
`
`This section provides an overview of general issues in cancer drug development. A discussion of
`
`commonly used cancer endpoints is followed by a discussion of pertinent issues in cancer
`
`clinical trial design using these endpoints (future guidances will discuss specific treatment
`
`indication endpoints). The endpoints that are discussed in this section include overall survival,
`
`endpoints based on tumor assessments (e.g., DFS, ORR, complete response, time to progression
`
`(TTP), progression-free survival (PFS)), and endpoints based on symptom assessment. Table 1
`
`provides a comparison of endpoints in cancer drug approval. Many issues relating to the proper
`
`analysis of efficacy endpoints are addressed in the ICH guidance for industry E9 Statistical
`
`Principles for Clinical Trials.
`
`
`
`Table 1. A Comparison of Important Cancer Approval Endpoints
`
`Endpoint
` Regulatory
`Study Design
`Advantages
`Evidence
`
`Disadvantages
`
`
`
`• May involve larger studies
`• May be affected by
`
`crossover therapy and
`sequential therapy
`
`• Includes noncancer deaths
`
`
`• Blinding is often difficult
`
`
`• Data are frequently missing
`
`or incomplete
`
`• Clinical significance of
`small changes is unknown
`
`• Multiple analyses
`• Lack of validated
`
`instruments
`
`• Not statistically validated as
`surrogate for survival in all
`
`settings
`
`• Not precisely measured;
`subject to assessment bias,
`
`particularly in open-label
`studies
`
`
`
`• Definitions vary among
`studies
`
`
`
`continued
`
`
`• Universally
`accepted direct
`
`measure of benefit
`
`
`
`• Easily measured
`
`
`• Precisely
`measured
`
`
`
`• Patient perspective
`of direct clinical
`
`benefit
`
`
`
`• Randomized
`studies essential
`• Blinding not
`
`essential
`
`
`
`Overall
`Survival
`
`Clinical benefit
`for regular
`approval
`
`
`Clinical benefit
`for regular
`
`approval
`
`
`• Randomized
`
`
`ibl nde ud st id es
`
`
`
`
`
`• Smaller sample
`size and shorter
`
`follow-up
`necessary
`compared with
`survival studies
`
`
`
`
`
`• Randomized
`studies essential
`• Blinding preferred
`
`• Blinded review
`recommended
`
`
`Surrogate for
`accelerated
`
`approval or
`regular
`
`approval*
`
`4
`
`
`Symptom
`Endpoints
`(patient-
`
`reported
`outcomes)
`
`Disease-Free
`Survival
`
`
`
`
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`Table 1, continued
`Endpoint
` Regulatory
`
`Evidence
`
`Contains Nonbinding Recommendations
`
`
`
` Study Design
`
`Advantages
`
`Disadvantages
`
`
`
`
`• Not statistically validated as
`surrogate for survival in all
`settings
`
`
`• Not precisely measured;
`subject to assessment bias
`particularly in open-label
`
`studies
`
`• Definitions vary among
`
`
`studies
`
`• Frequent radiological or
`
`
`other assessments
`
`• Involves balanced timing of
`
`assessments among
`treatment arms
`
`
`
`
`
`
`
`• Single-arm or
`randomized
`
`studies can be
`used
`
`
`• Blinding
`preferred in
`
`comparative
`studies
`
`• Blinded review
`
`recommended
`
`
`• Single-arm or
`randomized
`
`studies can be
`used
`
`
`• Blinding
`preferred in
`
`comparative
`studies
`
`• Blinded review
`
`recommended
`
`
`
`• Rand iom zed
`
`studies essential
`• Blinding
`preferred
`• Blinded review
`
`recommended
`
`Objective
`Response
`
`Rate
`
`Surrogate for
`
`accelerated
`approval or
`
`regular approval*
`
`
`
`Complete
`Response
`
`
`
`Surrogate for
`
`accelerated
`approval or
`
`regular approval*
`
`
`agrro te for
`Su
`
`
`accelerated
`approval or
`
`regular approval*
`
`
`Progression-
`Free Survival
`(includes all
`deaths)
`or
`Time to
`Progression
`
`(deaths before
`
`progression
`
`censored)
`
`
`• Not a direct measure of
`benefit
`
`• Not a comprehensive
`measure of drug activity
`bset
`• Only a su
` of patients
`
`
`who benefit
`
`
`
`
`
`
`
`• Can be assessed in
`
`single-arm studies
`
`• Assessed earlier
`and in smaller
`studies compared
`with survival
`studies
`
`• Effect attributable
`to drug, not natural
`
`
`history
`
`
`
`
`• Not a direct measure of
`benefit in all cases
`• Not a comprehensive
`measure of drug activity
`• Small subset of patients
`
`with benefit
`
`
`
`• Can be assessed in
`
`single-arm studies
`
`• Durable complete
`responses can
`represent clinical
`benefit
`
`
`• Assessed earlier
`and in smaller
`studies compared
`with survival
`studies
`
`• Smaller sam e lp
`
`size and shorter
`follow-up
`
`necessary
`compared with
`survival studies
`
`• Measurement of
`stable disease
`
`included
`
`• Not affected by
`crossover or
`subsequent
`
`therapies
`
`• Generally based on
`
`objective and
`quantitative
`assessment
`*Adequacy as a surrogate endpoint for accelerated approval or regular approval is highly dependent upon other factors such as
`
`
`
`
`effect size, effect duration, and benefits of other available therapy. See text for details.
`
`
`
`A.
`
`Overall Survival
`
`Overall survival is defined as the time from randomization until death from any cause, and is
`measured in the intent-to-treat population. Survival is considered the most reliable cancer
`endpoint, and when studies can be conducted to adequately assess survival, it is usually the
`preferred endpoint. This endpoint is precise and easy to measure, documented by the date of
`
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`death. Bias is not a factor in endpoint measurement. Survival improvement should be analyzed
`as a risk-benefit analysis to assess clinical benefit.
`
`Overall survival should be evaluated in randomized controlled studies. Data derived from
`
`historical trials are seldom reliable for time-dependent endpoints (e.g., overall survival, PFS).
`Apparent differences in outcome between historical controls and current treatment groups can
`arise from differences other than drug treatment, including patient selection, improved imaging
`techniques, or improved supportive care. Randomized studies minimize the effect of these
`differences by providing a direct outcome comparison. Demonstration of a statistically
`significant improvement in overall survival can be considered to be clinically significant if the
`toxicity profile is acceptable, and has often supported new drug approval.
`
`Difficulties in performing and analyzing survival studies include long follow-up periods in large
`trials and subsequent cancer therapy potentially confounding survival analysis.
`
`B.
`
`Endpoints Based on Tumor Assessments
`
`
`
`This section discusses several endpoints that are based on tumor assessments. These endpoints
`include DFS, ORR, TTP, PFS, and time-to-treatment failure (TTF). The collection and analysis
`of data on these time-dependent endpoints are based on indirect assessments, calculations, and
`estimates (e.g., tumor measurements). PFS data collection and analysis is supplemented by the
`tables shown in Appendix 3.
`
`Tumor-assessment endpoints selection should include two judgments. First, a determination of
`whether the endpoint will support either accelerated approval or regular approval should be
`ascertained. Second, the endpoint should be evaluated for the potential of bias or uncertainty in
`tumor endpoint assessments. Drug applications using studies that rely on tumor measurement-
`based endpoints as sole evidence of efficacy may need confirmatory evidence from a second
`trial. Accuracy in measuring tumors can differ among tumor settings. Tumor measurements
`used in response rate determinations can be imprecise in locations where there is a lack of
`
`demarcated margins (e.g., malignant mesothelioma, pancreatic cancer, brain tumors).
`
`When the primary study endpoint is based on tumor measurements (e.g., PFS or ORR), tumor
`endpoint assessments generally should be verified by central reviewers blinded to study
`treatments (see Appendix 4). This measure is especially important when the study itself is not
`blinded. It may be appropriate for the FDA to audit a sample of the scans to verify the central
`review process. Additional details regarding data collection are listed in Appendix 1.
`Centralized independent verification of tumor endpoint assessments (especially for PFS or DFS)
`may not be necessary when randomized trials are blinded (unless the adverse event profile would
`substantially unblind the trial in practice) or effect sizes are robust in large randomized trials
`
`where sensitivity analysis supports lack of observer bias (especially for DFS).
`
`
`
`1.
`
`Disease-Free Survival
`
`Generally, DFS is defined as the time from randomization until recurrence of tumor or death
`from any cause. The most frequent use of this endpoint is in the adjuvant setting after definitive
`
`
`
`6
`
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`surgery or radiotherapy. DFS also can be an important endpoint when a large percentage of
`patients achieve complete responses with chemotherapy. Although overall survival is a
`conventional endpoint for most adjuvant settings, DFS can be an important endpoint in situations
`where survival may be prolonged, making a survival endpoint impractical. DFS has been the
`primary basis of approval for adjuvant breast cancer hormonal therapy, adjuvant colon cancer,
`and adjuvant cytotoxic breast cancer therapy. Compared with standard cytotoxic therapies,
`hormonal therapies carry minimum side effects and thus a favorable risk-benefit relationship.
`DFS can be a surrogate for clinical benefit or it can provide direct evidence of clinical benefit.
`This determination is based on the magnitude of the effect, its risk-benefit relationship, and the
`disease setting. However, in disease settings where survival benefit has been already established,
`it is unlikely that DFS can be considered a clinical benefit. In December 2003, the ODAC
`consensus was DFS prolongation represented clinical benefit if the magnitude of this benefit
`outweighed the toxicity of the adjuvant treatment. In May 2004, the ODAC recommended that
`DFS be considered an acceptable endpoint for colon cancer drugs in the surgical adjuvant
`setting.7
`
`
`Important considerations in evaluating DFS as a potential endpoint include the estimated size of
`the treatment effect and proven benefits of standard therapies. The protocol should carefully
`delineate both the definition of DFS and the schedule for follow-up studies and visits.
`Unscheduled assessments can occur for many reasons and differences between study arms in the
`frequency, timing, or reason for unscheduled assessments can introduce bias. Bias can be
`minimized by blinding patients and investigators to the treatment assignments. The potential
`effects of bias due to unscheduled assessments can be evaluated by a comparative analysis of the
`total number of events over the follow-up period regardless of when the events occurred.
`
`The definition of DFS can be complicated, particularly when deaths are noted without prior
`tumor progression documentation. These events can be scored either as disease recurrences or as
`censored events. Although all methods for statistical analysis of deaths have some limitations,
`considering all deaths (deaths from all causes) as recurrences can minimize bias. DFS can be
`overestimated using this definition, especially in patients who die after a long period without
`observation. Bias can be introduced if the frequency of long-term follow-up visits is dissimilar
`between the study arms or if dropouts are not random because of toxicity. Some analyses count
`cancer-related deaths as DFS events and censor noncancer deaths. This method can introduce
`bias in the attribution of the cause of death. Furthermore, any method that censors patients,
`whether at death or at the last visit, assumes that the censored patients have the same risk of
`
`
`recurrence as noncensored patients.
`
`
`2.
`
`Objective Response Rate
`
`ORR is defined as the proportion of patients with tumor size reduction of a predefined amount
`and for a minimum time period. Response duration usually is measured from the time of initial
`response until documented tumor progression. Generally, the FDA has defined ORR as the sum
`of partial responses plus complete responses. When defined in this manner, ORR is a direct
`measure of drug antitumor activity, which can be evaluated in a single-arm study. Stable disease
`should not be a component of ORR. Stable disease can reflect the natural history of disease,
`
` 7 Transcripts are available at http://www.fda.gov/cder/drug/cancer_endpoints/default.htm.
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`whereas tumor reduction is a direct therapeutic effect. Also, stable disease can be more
`accurately assessed by TTP or PFS analysis (see below). If available, standardized criteria
`should be used to ascertain response. A variety of response criteria have been considered
`appropriate (e.g., RECIST criteria) (Therasse and Arbuck et al., 2000, New Guidelines to
`Evaluate Response to Treatment in Solid Tumors, J Natl Cancer Inst, 92:205-16). The response
`criteria should be predefined in the protocol before the start of the study. The significance of
`ORR is assessed by its magnitude and duration, and the percentage of complete responses (no
`detectable evidence of tumor).
`
`3.
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`Time to Progression and Progression-Free Survival
`
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`
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`TTP and PFS have served as primary endpoints for drug approval. TTP is defined as the time
`from randomization until objective tumor progression; TTP does not include deaths. PFS is
`defined as the time from randomization until objective tumor progression or death. The precise
`definition of tumor progression is important and should be carefully detailed in the protocol.
`
`a.
`
`TTP vs. PFS
`
`
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`Compared with TTP, PFS is the preferred regulatory endpoint. PFS includes deaths and thus can
`
`be a better correlate to overall survival. In TTP analysis, deaths are censored, either at the time
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`of death or at an earlier visit representing informative censoring (nonrandom pattern of loss from
`the study). PFS assumes patient deaths are randomly related to tumor progression. However, in
`situations where the majority of deaths are unrelated to cancer, TTP can be an acceptable
`
`endpoint.
`
`
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`b.
`
`PFS as an endpoint to support drug approval
`
`Table 1 provides advantages and disadvantages of using PFS as an endpoint. PFS can reflect
`tumor growth and be assessed before the determination of a survival benefit. Its determination is
`not confounded by subsequent therapy. For a given sample size, the magnitude of effect on PFS
`can be larger than the effect on overall survival. However, the formal validation of PFS as a
`surrogate for survival for the many different malignancies that exist can be difficult. Data are
`usually insufficient to allow a robust evaluation of the correlation between effects on survival
`and PFS. Cancer trials are often small, and proven survival benefits of existing drugs are
`generally modest. The role of PFS as an endpoint to support licensing approval varies in
`different cancer settings. Whether an improvement in PFS represents a direct clinical benefit or
`a surrogate for clinical benefit depends on the magnitude of the effect and the risk-benefit of the
`new treatment compared to available therapies.
`
`
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`c.
`
`PFS trial design issues
`
`The methodology for assessing, measuring, and analyzing PFS should be detailed in the protocol
`and statistical analysis plan (SAP). It is also important to carefully define tumor progression
`criteria in the protocol. There are no standard regulatory criteria for defining progression.
`Applicants have used a variety of different criteria, including the RECIST criteria. The broad
`outline presented in most published PFS criteria should be supplemented with additional details
`in the protocol and SAP. Visits and radiological assessments should be symmetric between the
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`• The study design
`• The definition of progression
`• The data to be recorded on the case report form (CRF)
`• The SAP
`• The methodology for handling missing data and censoring methods
`• The operating procedures of an independent endpoint review committee (IRC), if
`
`applicable (see Appendix 4)
`
`
`d.
`
`Analysis of PFS
`
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`two study arms to prevent systematic bias. When possible, studies should be blinded. Blinding
`is particularly important when patient or investigator assessments are included as components of
`the progression endpoint. At a minimum, the assessments should be subjected to a blinded
`independent adjudication team, generally consisting of radiologists and clinicians. The FDA and
`the applicant should agree prospectively on the following items:
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`Missing data can complicate analysis of PFS. The protocol should define a